In the formal validation, the Subunit 'Clinical Pharmacology' inspects the application form “Request for Authorisation” (parts E and F) with regard to mistakes or inconsistencies. Furthermore, the following documents are examined with respect to the requirements of Section 7 of the GCP Ordinance:

• Has a protocol been submitted? (Section 7 sub-section 2 number 3 GCP Ordinance)
• Has an Investigator’s Brochure (IB) been submitted? (Section 7 sub-section 2 number 7 GCP Ordinance)
• Is there an investigational medicinal product dossier (IMPD) for the investigational medicinal products which have no marketing authorisation within the European Union? Or is there a simplified IMPD, e.g. a Summary of Product Characteristics (SmPC), for investigational medicinal products which have a marketing authorisation within the European Union (Section 7 sub-section 4 number 1 and Section 7 sub-section 5 GCP Ordinance)
• Does the protocol include information on the subject of the clinical trial and its objectives (Section 7 sub-section 2 number 9 GCP Ordinance)
• Does the protocol include information on the number, age, and sex of the trial subjects? (Section 7 sub-section 2 number 6 GCP Ordinance)
• Is there an explanation of the criteria for the selection of trial subjects and the underlying statistical considerations? (Section 7 sub-section 2 number 11 GCP Ordinance)
• Is there a justification why the chosen sex distribution in the group of trial subjects is appropriate to identify possible sex-specific differences in the efficacy and safety of the investigational medicinal product being tested? (Section 7 sub-section 2 number 12 GCP Ordinance)
• Is there a plan for the further treatment and medical care of the trial subjects after completion of the clinical trial? (Section 7 sub-section 2 number 13 GCP Ordinance)

Following the examination of document completeness, the documents will be examined with regard to their content.

Often, there is no justification pursuant to Section 7 sub-section 2 number 12 of the GCP Ordinance specifying the appropriateness of the chosen sex distribution of trial subjects for detecting possible sex-specific differences in the efficacy and safety of the investigational medicinal product being tested. Furthermore, applicants should bear in mind that pursuant to Section 7 sub-section 2 number 13 of the GCP Ordinance, a plan for the further treatment and medical care of the trial subjects after completion of the clinical trial is to be attached to the application.

In this context, applicants can specify that in the course of data analysis, stratification according to sex will be performed. If no sex-specific differences are meant to be investigated within the clinical trial, there should be an explanation for this. Should medicinal products be tested, for which sex-specific differences in efficacy or safety have already been investigated, this can be pointed out. No such justification is necessary for clinical trials enrolling only men or only women.

In this context, applicants should describe which medical treatment the trial subjects will receive after completion of the clinical trial. Normally, patients will continue to receive their standard therapy or they will continue to be treated by their general practitioner. As a general rule, no further treatment is necessary for healthy subjects. However, we ask for a brief comment on this. Alternatively, this information can be stated in the application form under Section F.5 “Plans for treatment or care after a subject has ended...”.

The cover letter shall state that it is intended to include minors in the clinical trial. We recommend describing as early as in the cover letter, how the following regulations will be implemented:

Pursuant to Section 40 sub-section 4 number 2 of the German Medicines Act, a paediatric trial may only be conducted if clinical trials performed on adults or other research methods cannot be expected to produce satisfactory test results according to medical knowledge.

Pursuant to Section 40 sub-section 4 number 4 of the German Medicines Act, a paediatric trial may only be conducted if it subjects the person concerned to as little burden and other foreseeable risks as possible; both the degree of burden and the risk threshold must be defined specifically in the trial protocol and must be monitored constantly by the investigator. In addition, the protocol must include a description of how this constant monitoring of the degree of burden and the risk threshold will be performed by the investigator.

In the cover letter, it should be mentioned that within the clinical trial a medicinal product is meant to be administered in humans for the first time. In this context, it should already be discussed whether the medicinal product is a potential high-risk substance (e. g. administration of a class of substances for the first time, novel mode of action, intervention in the immune system). This case must be differentiated from clinical trials with new formulations of an active substance for which experience with regard to administration in humans already exists.

First-in-man clinical trials involving a novel substance require a critical discussion in the trial protocol of whether the novel substance is a potential high-risk medicinal product. The draft GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE RISKS FOR FIRST-IN-HUMAN CLINICAL TRIALS WITH INVESTIGATIONAL MEDICINAL PRODUCTS outlines three criteria which classify an active substance as a high-risk substance:

• New or not exactly known mode of action; in this context, a pleiotropic mechanism (e. g. leading to various physiological effects) is considered as high risk, or targets that are ubiquitously expressed, as often seen in the immune system.
• New or not exactly known structure and biological function of the target; most newly developed active substances act on a single target, e. g. a receptor or a physiological reaction. Caution should be exercised when the exact structure and biological function of the target as well as its tissue distribution are not exactly known.
• Relevance of the animal studies which preceded the first-in-man clinical trial; in this context, sponsors should ensure to chose an animal model which corresponds with humans to a great extent, pharmacologically and toxicologically.

For active substances which can potentially cause severe adverse reactions upon first-in-man administration, dosing should no longer be based exclusively on the „No Observed Adverse Effect Level“ (NOAEL), but on the „Minimal Anticipated Biological Effect Level“ (MABEL). Detailed reasons shall be given for the initial dose, the dose increases and the maximum dose. In first-in-man clinical trials, careful consideration should be given to the question whether an intravenous administration is necessary. If so, the active substance should be administered as slowly as possible. Thus, the infusion can be timely discontinued in the case of adverse reactions. Moreover, the number of participants exposed simultaneously is to be kept as low as possible (sequential design). Furthermore, the clinical trial protocol should describe in detail the requirements for a dose increase and the measures that will be taken in a medical emergency.

Pursuant to Directive 2005/28/EC of the Commission dated 8 April 2005 Article 8 (3), the sponsor shall validate and update the Investigator’s Brochure, if necessary, at least once a year. If an update of the Investigator’s Brochure is not considered necessary, it is recommended to notify the competent national authority of this fact. If the amendments to the Investigator’s Brochure are liable

1. to affect the safety of the trial subjects (positively or negatively) or
2. to influence the interpretation of the scientific documents on which the trial is based or the scientific value of the study results, the amended Investigator’s Brochure must be submitted to the competent national authority as a substantial amendment.

Insofar as the amendments made are not subject to approval pursuant to Section 10 sub-section 1 sentence 2 numbers 1 and 2 of the GCP Ordinance, it is nonetheless recommended to promptly submit the new Investigator’s Brochure to the competent national authority for information.

In accordance with Directive 2001/20/EC, the principle "Each clinical trial must have a primary question" must be observed in clinical trials. In this context, a clinical trial may include several parts, provided the principle of a single confirmatory question is basically adhered to. Thus, in the early stage of development, several parts may be combined in a clinical trial (e.g. single dose, multiple doses, food-drug interactions).

In such cases, a maximal dose or a maximal exposure should be defined in the protocol. Safety margins with regard to the relevant animal species should be discussed in the risk-benefit assessment. In addition, criteria for the decision on dose escalation increments should be specified in the protocol. In this context there could be a description, for example, that dose escalation will be stopped at the latest when minimum intolerable dose (MID) or maximum tolerable dose (MTD) have been reached. In individual cases, the national competent authority will order presentation of safety reports pursuant to Section 13 sub-section 6 of the GCP Ordinance (e. g. prior to starting multiple dosing).

For investigational medicinal products which have the potential of causing severe adverse reactions upon first administration in man in accordance with the GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE RISKS FOR FIRST-IN-HUMAN CLINICAL TRIALS WITH INVESTIGATIONAL MEDICINAL PRODUCTS, “integrated” protocols are not appropriate. It should be borne in mind that the administrative effort is higher for “integrated” protocols; hence, increased costs depending on the administrative effort will be charged.